Synthesis and Suzuki-Miyaura reactions of 3,6,8-tribromoquinoline: A structural revision

Article abstract of DOI:10.1055/s-0032-1316904

It was earlier reported that the bromination of 1,2,3,4-tetrahydroquinoline with NBS would give 4,6,8-tribromoquinoline. This reaction was reinvestigated, and the structure was assigned to be 3,6,8-tribromoquinoline. Suzuki-Miyaura cross-coupling reactions of this molecule allowed for a convenient synthesis of 3,6,8-triarylquinolines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316904

LETTER
▌1121
lSetyternthesis and Suzuki–Miyaura Reactions of 3,6,8-Tribromoquinoline:
A Structural Revision
Synthesis and Suzuki–Miyaura Reactions of 3,6,8-Tribromoquinoline
Omer A. Akrawi,a,b Hamid H. Mohammed,a,c Peter Langer*a,d
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Department of Chemistry, College of Science, University of Mosul, Mosul, Iraq
c
Department of Chemistry, College of Science, University of Al-Mustansiryah, Baghdad, Iraq
d
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received: 11.03.2013; Accepted: 17.03.2013
3,6,8-tribromoquinoline and not, as previously reported,19
4,6,8-tribromoquinoline. In addition, we report the first
Suzuki–Miyaura reactions of this substrate.
Abstract: It was earlier reported that the bromination of 1,2,3,4-tet-
rahydroquinoline with NBS would give 4,6,8-tribromoquinoline.
This reaction was reinvestigated, and the structure was assigned to
be 3,6,8-tribromoquinoline. Suzuki–Miyaura cross-coupling reac-
tions of this molecule allowed for a convenient synthesis of 3,6,8-
triarylquinolines.
O
Key words: catalysis, heterocycles, palladium, cross-coupling re-
MeO
actions, nitrogen, quinoline
N
CONHNH2
MeO
N
Quinoline derivatives are found in many natural products1
and synthetic drugs.2 In fact, several quinolines exhibit
important pharmacological activities,3 such as antiasth-
matic, anti-inflammatory and antimalarial,4 anticancer,5
and antibiotic activity (examples include quinolines A–C
shown in Figure 1).6 In addition, they are used in material
science as dyestuffs and photographic sensitizers.7 They
are valuable reagents for the synthesis of nano- and meso-
structures with enhanced electronic and photonic proper-
ties.8 Arylated quinolines were previously prepared by
classic reactions, such as the Skraup, Doebner–Miller,
Conrad–Limpach, Friedländer, and Pfitzinger syntheses.9
Arylated quinolines are also available by Suzuki–Miyaura
cross-coupling reactions and other transition-metal-cata-
lyzed transformations.10,11 For example, arylated quino-
lines were prepared by Stille coupling of aryl triflates with
organostananes,12 and by nickel-catalyzed reaction of ar-
ylzinc halides with quinoline nonaflates.13 The Kumada–
Tamao–Corriu reaction was applied to the synthesis of 5-
arylquinolines.14 Nickel-catalyzed cross-coupling reac-
tions of quinoline carbamates with arylboroxines have
been used to prepare 5- and 6-arylquinolines.15 A number
of 7-arylquinolines were prepared by palladium-catalyzed
coupling of quinolinylboronic esters with aryl halides.16
Recently, 5,7-diarylquinolines were prepared by Suzuki–
Miyaura reactions of 5,7-dihalogenated quinolines.17 Re-
cently, we have reported the synthesis of arylated quino-
lines by Suzuki–Miyaura reactions of 5,7-dibromo-8-
(trifluoromethylsulfonyloxy)quinoline.18 Herein, we re-
port a reinvestigation of the bromination of 1,2,3,4-tetra-
hydroquinoline with an excess of NBS which afforded
A
B
NH2
N
N
N
N
R
C
Figure 1 Some pharmacologically active quinolines
A number of brominated quinoline derivatives are known
which represent valuable starting materials for palladium-
catalyzed cross-coupling reactions. 3-Bromoquinoline is
available in 82% yield by heating the quinoline–bromine
adduct in an inert solvent with pyridine as the hydrogen
bromide scavenger.20 In 2008, Sahin et al. reported that
the reaction of 1,2,3,4-tetrahydroquinoline (1) with five
equivalents of NBS in the presence of AIBN in CHCl3
(r.t., irradiation with a 70 W sun lamp) afforded 4,6,8-tri-
bromoquinoline (2) in 75% yield.19 The same product was
obtained, albeit in lower yield, when CCl4 was used as the
solvent. The authors also reported that the reaction of
1,2,3,4-tetrahydroquinoline with bromine in chloroform
at –20 °C gave 6,8-dibromo-1,2,3,4-tetrahydroquinoline
(3) which was transformed by DDQ to 6,8-dibromo-
1,2,3,4-tetrahydroquinoline. In 2010, Celik et al. reported
the transformation of 3 to 3,6,8-tribromoquinoline (4) in
90% yield by employment of bromine (3 equiv) and chlo-
roform as the solvent (r.t., 3 d).21 The structure of the
product was confirmed by X-ray crystal-structure analy-
sis, and its melting point was identical with that of the
product isolated by Sahin. Surprisingly, the authors did
not comment the fact that a different isomer was obtained
as compared to the work of Sahin, presumably because
they accounted this difference to the use of different start-
SYNLETT 2013, 24, 1121–1124
Advanced online publication: 18.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316904; Art ID: ST-2013-D0218-L
© Georg Thieme Verlag Stuttgart · New York

1122
O. A. Akrawi et al.
LETTER
ing materials, brominating agents, and reaction condi-
tions.
7.78H
H8.14
We reinvestigated the work of Sahin and co-workers and
found that the reaction of 1 with six equivalents of NBS in
the presence of AIBN in benzene resulted in the formation
of a tribrominated quinoline in 98% yield (Scheme 1).22 In
contrast to Sahin et al., we carried out the reaction under
reflux for 12 hours (instead of room temperature and sun
lamp irradiation), we used benzene instead of chloroform
as the solvent and we used six instead of five equivalents
of NBS. However, we also carried out the reaction in CCl4
(as reported by Sahin et al.) and obtained the same prod-
uct, albeit in lower yield. Detailed NMR investigations re-
vealed that the structure of the product was 3,6,8-
tribromoquinoline (4) and not 4,6,8-tribromoquinoline (2)
as reported by Sahin and co-workers. In fact, the melting
point of our product (170–172 °C) was very close to the
Br
Br
8.06H
N
H8.90
Br
Figure 2 NOESY correlations of 4
The Suzuki–Miyaura reaction of 4 with arylboronic acids
5a–r (3.5 equiv) afforded 3,6,8-triarylquinolines 6a–r
(Scheme 2, Table 1).23 The best yields were obtained
when the reactions were carried out using Pd(PPh3)4 as the
catalyst and K2CO3 as the base (1,4 dioxane, 80–95 °C, 4–
6 h). Both electron-rich and electron-poor arylboronic ac-
ids were successfully employed. The yields of the prod-
ucts derived from arylboronic acids containing electron-
withdrawing substituents, which are less nucleophilic,
were lower than the yields of products derived from aryl-
boronic acids containing electron-donating substituents.
Unfortunately, all attempts to develop regioselective Su-
zuki–Miyaura reactions failed, due to the similar electron-
ic and steric properties of all three positions.
1
one reported by Sahin (168–170 °C). In addition, the H
NMR and 13C NMR data were nearly identical. Sahin and
co-workers reported that they carried out COSY and
HETCOR experiments, but NOESY experiments were
not mentioned. To unambiguously confirm the structure,
we have carried out NOESY experiments and observed a
diagnostic NOESY correlation between hydrogen atoms
H-4 and H-5 which is possible for isomer 4, but not for
isomer 2 (Figure 2). In addition, our results better explain
the small coupling constants in the range of 2 Hz which
are more typical for a 4J and not for a 3J coupling. In fact,
the 4J = 2.2 Hz coupling between protons H-2 and H-4 is
in full accordance with structure 4, but would be rather
Table 1 Synthesis of 6a–r
3, 4
Ar
Yield of 6 (%)a
a
b
c
d
e
f
Ph
92
72
87
63
55
88
77
55
63
75
56
66
75
77
64
82
64
77
4-MeOC6H4
4-MeC6H4
3-MeC6H4
4-t-BuC6H4
3,5-Me2C6H3
3,4-Me2C6H3
4-F3CC6H4
4-FC6H4
3
small for a J coupling between protons H-2 and H-3 of
structure 2. In the light of our data and of the findings of
Celik and co-workers, we assume that Sahin et al. also had
obtained 3,6,8-tribromoquinoline, but wrongly assigned
the structure to be 4,6,8-tribromoquinoline. Accordingly,
the structure of the products of the follow-up chemistry of
this product have to be revised.
g
h
i
Br
Br
ref. 19
j
3-FC6H4
N
k
l
4-ClC6H4
Br
2
N
3-ClC6H4
i
Br
Br
H
our
work
1
m
n
o
p
q
r
2-MeC6H4
2-MeOC6H4
2,3-(MeO)2C6H3
2,5-(MeO)2C6H3
2,6-(MeO)2C6H3
2,6-Me2C6H3
N
Br
4
97%
Br
N
H
Br
3
a Yields of isolated products.
Scheme 1 Synthesis of 4. Reagents and conditions: i) 1 (1.0 equiv),
NBS (6.0 equiv), AIBN (20 mol%), dry benzene, reflux 12 h.
Synlett 2013, 24, 1121–1124
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis and Suzuki–Miyaura Reactions of 3,6,8-Tribromoquinoline
1123
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ArB(OH)2
5a–r
Br
Br
Ar
Ar
N
N
i
Br
Ar
6a–r
4
Scheme 2 Synthesis of 6a–r. Reagents and conditions: i) 4 (1.0
equiv), ArB(OH)2 (3.5 equiv), Pd (PPh3)4 (9 mol%), K2CO3 (2 M,
2 mL), 1,4-dioxane (2 mL), 80–95 °C, 4–6 h.
In conclusion, we have reported a structural revision of a
previous report which claimed that the bromination of
1,2,3,4-tetrahydroquinoline with NBS would give 4,6,8-
tribromoquinoline. Detailed 2D NMR studies revealed
that the product has to be assigned to be 3,6,8-tribromo-
quinoline. In addition, a new application of this molecule,
namely Suzuki–Miyaura cross-coupling reactions, were
reported which allowed for a convenient synthesis of
3,6,8-triarylquinolines. Regioselective cross-coupling
reactions failed.
(17) (a) Sahu, K. B.; Hazra, A.; Paira, P.; Saha, P.; Naskar, S.;
Paira, R.; Banerjee, S.; Sahu, N. P.; Mondal, N. B.; Luger,
P.; Weber, M. Tetrahedron 2009, 65, 6941. (b) Sliman, F.;
Desmaele, D. Synthesis 2010, 619.
(18) Eleya, N.; Mahal, A.; Hein, M.; Villinger, A.; Langer, P.
Adv. Synth. Catal. 2011, 353, 2761.
(19) Sahin, A.; Cakmak, O.; Demirtas, I.; Okten, S.; Tutar, A.
Tetrahedron 2008, 64, 10068.
(20) Eisch, J. J. J. Org. Chem. 1962, 27, 1318.
References and Notes
(1) (a) Morimoto, Y.; Matsuda, F.; Shirahama, H. Synlett 1991,
202. (b) Balasubramania, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II; Vol. 5; Katritzky, A. R.; Rees,
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J. Med. Chem. 1994, 37, 2129. (d) Kalluraya, B.; Sreenivasa,
S. Farmaco 1998, 53, 399. (e) Roma, G.; Braccio, M. D.;
Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000,
1021. (f) Chen, Y. L.; Fang, K.-M.; Sheu, J.-Y.; Hsu, S.-L.;
Tzeng, M. J. Med. Chem. 2001, 44, 2374.
(21) Celik, I.; Akkurt, M.; Okten, S.; Cakmak, O.; Granda, S. G.
Acta Crystallogr., Sect. E.: Struct. Rep. Online 2010, 66,
o3133.
(22) Synthesis of 3,6,8-Tribromoquinoline (4)
To a solution of 1,2,3,4-tetrahydroquinoline (1, 0.5 g, 3.76
mmol) in dry benzene (50 mL), NBS (4.0 g, 22.5 mmol, 6
equiv), and AIBN (0.12 g, 0.75 mmol, 20 mol%) were added
under an argon atmosphere, and the reaction mixture was
stirred under reflux for 12 h. The reaction was monitored by
TLC (EtOAc–heptanes, 0.5:9.5). After cooling, distilled
H2O (5 mL) and Et3N (1 mL) were added, then the organic
layer was extracted with EtOAc. The combined organic
layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc–heptanes, 10:0.1) to
give 4 as a white solid (1.36 g, 98%); mp 170–172 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.78 (d, 1 H, J = 1.8 Hz, ArH),
8.06 (d, 1 H, J = 2.0 Hz, ArH), 8.14 (d, 1 H, J = 2.2 Hz, ArH),
8.90 (d, 1 H, J = 2.2 Hz, ArH). 13C NMR (75.5 MHz,
CDCl3): δ = 119.3, 121.2, 126.0 (C), 128.7 (CH), 130.6 (C),
136.2, 136.6 (CH), 142.3 (C), 152.4 (CH). IR (KBr): ν =
3086, 3074, 3052 (w), 1588, 1579, 1568, 1540, 1504, 1488
(m), 1456 (s), 1410, 1384, 1354, 1327, 1316, 1305, 1262,
1233, 1197, 1173, 1146 (m), 1082 (br), 1071 (br), 967 (br),
924 (w), 903 (s), 894 (s), 871, 855, 814 (m), 779 (s), 680 (s),
648, 615, 594 (m), 526 (s) cm–1. GC–MS (EI, 70 eV): m/z
(%) = 369 (32) [M, 81Br81Br81Br]+, 367 (97) [M,
(3) Gottlieb, D.; Shaw, P. D. Antibiotics, Part II: Biosynthesis;
Springer: New York, 1967.
(4) Arcadi, A.; Chiarini, M.; Giuseppe, S. D.; Marinelli, F.
Synlett 2003, 203; and references cited therein.
(5) (a) Kaneko, T.; Romero, K.; Li, B.; Buzon, R. Bioorg. Med.
Chem. Lett. 2007, 17, 5049. (b) Mulvihill, M. J.; Ji, Q.-S.;
Coate, H. R.; Cooke, A.; Dong, H.; Feng, L.; Foreman, K.;
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M.; Nigro, A. I.; Connor, M. O.; Pirrit, M.; Steinig, A. G.;
Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.;
Gibson, N. W. Bioorg. Med. Chem. 2008, 16, 1359.
(6) (a) Altmann, K.-H.; Bold, G.; Caravatti, G.; Flçrsheimer, A.;
Guagnano, V.; Wartmann, M. Bioorg. Med. Chem. Lett.
2000, 10, 2765. (b) Nomura, T.; Iwaki, T.; Narukawa, Y.;
Uotani, K.; Hori, T.; Miwa, H. Bioorg. Med. Chem. 2006,
14, 3697.
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Macromolecules 1999, 32, 7422. (c) Jenekhe, S. A.; Lu, L.;
Alam, M. M. Macromolecules 2001, 34, 7315.
81Br81Br79Br]+, 365 (100) [M, 79Br79Br81Br]+, 363 (34) [M,
79Br79Br79Br]+, 286 (17), 205 (22), 178 (5). HRMS (ESI-
TOF/MS, 70 eV): m/z calcd for C9H5NBr3 [M + H,
79Br79Br79Br]+: 363.79666; found: 363.79681; calcd for
C9H5NBr3 [M + H, 81Br 79Br79Br]+: 365.79463; found:
365.79471; calcd for C9H5NBr3 [M + H, 81Br81Br79Br]+:
367.79261; found: 367.79279; calcd for C9H5NBr3 [M + H,
81Br81Br81Br]+: 369.79064; found: 369.79081.
(23) General Procedure for the Suzuki–Miyaura Reactions
A dioxane solution of 3,6,8-tribromoquinoline (4, 0.21
mmol), arylboronic acid (3.5 equiv), Pd(PPh3)4 (9 mol%),
and K2CO3 (2 M, 2 mL) was stirred at the indicated
temperature and for the indicated time under an argon
atmosphere. After cooling to 20 °C, distilled H2O was
(9) Jones, G. In Comprehensive Heterocyclic Chemistry; Vol. 2;
Katritzky, A. R.; Rees, W., Eds.; Pergamon Press: New
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and references cited therein.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1121–1124

1124
O. A. Akrawi et al.
LETTER
added. The organic and aqueous layers were separated, and
the latter was extracted with CH2Cl2. The combined organic
layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, EtOAc–heptanes).
Hz, ArH), 8.23 (d, 1 H, J = 2.3 Hz, ArH), 9.09 (d, 1 H, J =
2.3 Hz, ArH). 13C NMR (75.5 MHz, CDCl3): δ = 124.2,
126.2, 126.4, 126.5, 126.7, 127.0, 127.1 (CH), 127.7 (C),
127.9, 128.1, 128.9, 129.5 (CH), 132.4, 132.8 (C), 136.7
(CH), 138.3, 138.4, 139.1, 140.1, 143.4 (C), 148.5 (CH). IR
(KBr): ν = 3101, 3053, 3029 (w), 1596, 1477, 1442, 1376,
1344 (m), 1260 (w), 1177, 1153, 1075, 1022, 973 (m), 898,
805, 757, 694 (s), 614, 574, 546 (m) cm–1. GC–MS (EI, 70
eV): m/z (%) = 356 (100) [M+], 280 (6), 178 (4). HRMS
(ESI-TOF/MS, 70 eV): m/z calcd for C27H20N [M + H]+:
357.15903; found: 357.15950.
3,6,8-Triphenylquinoline (6a)
Starting with 1 (75 mg, 0.21 mmol), 5a (90 mg, 0.74 mmol),
Pd(PPh3)4 (21 mg, 9 mol%), K2CO3 (2 M, 2 mL), and
dioxane (2 mL), 6a was isolated as a white solid (65 mg,
92%); mp 174–176 °C (EtOAc–heptanes, 0.1:10). 1H NMR
(300 MHz, CDCl3): δ = 7.25–7.44 (m, 9 H, ArH), 7.59 (m, 6
H, ArH), 7.87 (d, 1 H, J = 2.0 Hz, ArH), 7.91 (d, 1 H, J = 2.0
Synlett 2013, 24, 1121–1124
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